The mechanisms governing Ca entry and exit in the myocardial cell have not been well defined. Ca entry is believed to occur as a slow inward current during the plateau phase of the action potential. In addition, there is evidence for the existence of a Na, Ca exchange system. Langer has suggested that this acts to bring Ca into the cell, while Reuter feels that it is a mechanism for Ca exit. Because Na, Ca exchange is reversible, it may promote both Ca entry or Ca exist at different stages of contraction-relaxation cycle or under different physiological or pharmacological conditions. It has been suggested that this putative Na, Ca exchange system is involved in the inotropic effect of cardiac glycosides and possibly of other inotropic agents. Recently, we have demonstrated Na, Ca-exchange in a cell-free vesicular preparation from dog heart, which is evidently of sarcolemmal origin because the same vesicles also exhibit sodium pump activity. The main thrust of this proposal is to study this Na, Ca exchange system in vesicular preparations from cardiac sarcolemma in order to determine its role, both in excitation-coupling in the heart and in the mechanism of action of digitalis. Kinetic studies of this system should indicate its stoichiometry, and the direction in which it operates in the intact cell. It will then be possible to test the effects on this system of cardiac glycosides, other inotropic agents and known inhibitors of myocardial Na and Ca fluxes. These studies should help to define the role of these sarcolemmal systems in the excitation-contraction process and in the pharmacologic control of cardiac muscle.